Bioabsorbable branched polymers containing units derived from dioxanone and medical/surgical devices manufactured therefrom

ABSTRACT

Star polymers of soft segment forming monomers are useful in forming surgical devices. The star polymers can be endcapped with isocyanate, mixed with a filler and/or cross-linked. The polymer compositions are useful, for example, as fiber coatings, surgical adhesives or bone putty, or tissue growth substrate.

RELATED APPLICATIONS

[0001] This application is a continuation-in-part of copendingapplication Ser. No. 08/477,098 filed Jun. 7, 1995, which is acontinuation-in-part of copending application Ser. No. 08/278,898 filedJul. 22, 1994. The entire disclosure of these two applications areincorporated herein by reference.

BACKGROUND OF THE INVENTION

[0002] 1. Technical Field

[0003] This disclosure relates generally to bioabsorbable polymercompositions. Specifically, this disclosure relates to highly branchedor star polymers derived from monomers known to form absorbablepolymers. The bioabsorbable polymer compositions are particularly usefulin the manufacture of absorbable surgical devices such as sutures,staples clips, anastomosis rings, bone plates and screws, matrices forthe sustained and/or controlled release of pharmaceutically activeingredients, etc., fabricated at least in part therefrom.

[0004] 2. Background of Related Art

[0005] Polymers and copolymers of, and surgical devices made from,lactide and/or glycolide and/or related compounds are well-known. See,e.g., U.S. Pat. Nos. 2,668,162, 2,683,136, 2,703,316, 2,758,987,3,225,766, 3,268,486, 3,268,487, 3,297,033, 3,422,181, 3,442,871,3,463,158, 3,468,853, 3,531,561, 3,565,869, 3,597,449, 3,620,218,3,626,948, 3,636,956, 3,736,646, 3,739,773, 3,772,420, 3,773,919,3,781,349, 3,784,585, 3,792,010, 3,797,499, 3,839,297, 3,846,382,3,867,190, 3,875,937, 3,878,284, 3,896,802, 3,902,497, 3,937,223,3,982,543, 4,033,938, 4,045,418, 4,057,537, 4,060,089, 4,137,921,4,157,437, 4,243,775, 4,246,904, 4,273,920, 4,275,813, 4,279,249,4,300,565, and 4,744,365, U.K. Pat. or Appln. Nos. 779,291, 1,332,505,1,414,600, and 2,102,827, D. K. Gilding et al., “Biodegradable polymersfor use in surgery-polyglycolic/poly (lactic acid) homo- and copolymers:1,” Polymer, Volume 20, pages 1459-1464 (1979), and D.F. Williams (ed.),Biocompatibility of Clinical Implant Materials, Volume II, chapter 9:“Biodegradable Polymers” (1981). All of the foregoing documents arehereby incorporated by reference.

[0006] In addition, other patents disclose surgical devices preparedfrom copolymers of lactide or glycolide and other monomers includingcaprolactone or trimethylene carbonate have been prepared. For example,U.S. Pat. No. 4,605,730 and U.S. Pat. No. 4,700,704 disclose copolymersof epsilon-caprolactone and glycolide useful in making surgical articlesand particularly surgical sutures having low Young's modulus. Inaddition, U.S. Pat. No. 4,624,256 relates to the utilization of highmolecular weight caprolactone polymers as coatings for surgical sutures,while U.S. Pat. No. 4,429,080 discloses surgical articles manufacturedfrom triblock copolymers prepared from copolymerizing glycolide withtrimethylene carbonate.

[0007] Polymers, copolymers and surgical devices made fromε-caprolactone and/or related compounds have also been described in U.S.Pat. Nos. 3,169,945, 3,912,692, 3,942,532, 4,605,730, 4,624,256,4,643,734, 4,700,704, 4,788,979, 4,791,929, 4,994,074, 5,076,807,5,080,665, 5,085,629 and 5,100,433.

[0008] Polymers derived in-whole or in part from dioxanone are known.Homopolymers of p-dioxanone are described, e.g., in U.S. Pat. Nos.3,063,967; 3,063,968; 3,391,126; 3,645,941; 4,052,988; 4,440,789; and,4,591,630. Copolymers containing units derived from p-dioxanone and oneor more other monomers that are copolymerizable therewith are described,e.g., in U.S. Pat. Nos. 4,243,775; 4,300,565; 4,559,945; 4,591,630;4,643,191; 4,549,921; 4,653,497; 4,791,929; 4,838,267; 5,007,923;5,047,048; 4,076,807; 5,080,665; and 5,100,433 and European PatentApplication Nos. 501,844 and 460,428. Most of the knowndioxanone-derived homopolymers and copolymers are indicated to be usefulfor the fabrication of medical and surgical devices such as thosepreviously mentioned.

[0009] The properties of the bioabsorbable polymers may differconsiderably depending on the nature and amounts of the comonomers, ifany, employed and/or the polymerization procedures used in preparing thepolymers. Aforementioned U.S. Pat. No. 4,838,267 discloses blockcopolymers derived from p-dioxanone and glycolide that exhibit a highorder of initial strength and compliance but lose their strength rapidlyafter implantation in the body. Sutures made from the copolymers aresaid to be particularly useful in surgical procedures, such as plasticsurgery or repair of facial wounds, where it is desirable for the sutureto lose its strength rapidly.

SUMMARY

[0010] The general formula of the novel polymers described herein is:

[0011] CH₂OR₁—(CHOR₂)—(CHOR₃)—(CHOR₄) . . . (CHOR)—CH₂OR_(n+1) wherein:n equals 1 to 13, preferably 2 to 8 and most preferably 2 to 6;

[0012] R₁, R₂ . . . R_(n+1) are the same or different and selected fromthe group of a hydrogen atom or (Z)_(m) wherein Z comprises repeatingunits selected from the group consisting of:

[0013] wherein p is 3 to 8 and each R′ may be the same or different andare individually selected from the group consisting of hydrogen andalkyl having from 1 to 5 carbon atoms, such that at least three of saidR₁, R₂ . . . R_(n+1) groups are other than hydrogen;

[0014] m is sufficient such that the star polymer has an inherentviscosity in HFPI at 25° C. between about 0.01 and about 0.5 dl/gm,preferably from about 0.15 to about 0.3 dl/gm, and most preferably fromabout 0.15 to about 0.2 dl/gm; and

[0015] the m's for each (Z) group may be the same or different.

[0016] The polymers are initiated with a polyhydric alcohol. Preferredinitiators are mannitol, pentaerythritol and threitol.

[0017] In a particularly useful embodiment, a bioabsorbable polymer ofthe foregoing general formula is provided wherein (Z) consistsessentially of repeating units of the formula:

[0018] and the polymer has an inherent viscosity between about 0.05 and0.5 dl/gram in HFIP at 25° C.

[0019] The polymers described herein are useful in the production ofsurgical devices. In particularly useful embodiments the polymers areused in coatings on surgical devices, such as, for example fibers usedto produce sutures, meshes, woven structures, etc.

[0020] The polymers may be endcapped with an isocyanate. The isocyanatecapped polymer may be cross-linked in the presence of water and/or acatalyst, such as tertiary amine catalyst. The cross-linked starpolymers are useful for example as bone adhesives or bone fillers.Optionally, the polymer may be mixed with a filler such ashydroxyapatite, tricalcium phosphate, bioglass or other bioceramic priorto cross-linking to produce a bone putty or a bone-growth-inducingsubstance to be packed into or used in conjunction with a bone fusionimplant.

[0021] Alternatively, after endcapping with an isocyanate, a charge maybe chemically induced on the polymer, such as, for example by reacting afraction of the available isocyanate groups with diethylene ethanolamine(DEAE) and then cross-linking at least a portion of the balance of theremaining available isocyanate groups to form a water-insoluble,degradable, charged particle. These charged compositions are useful forexample as an agent to enhance soft tissue wound healing.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

[0022] The general formula of the basic polymer in accordance with thisdisclosure is:

[0023] CH₂OR₁—(CHOR₂)—(CHOR₃)—(CHOR₄) . . . (CHOR₄)—CH₂OR_(n+1) wherein:n equals 1 to 13, preferably 2 to 8 and most preferably 2 to 6;

[0024] R₁, R₂ . . . R_(n+1) are the same or different and selected fromthe group of a hydrogen atom or (Z)_(m) wherein Z comprises repeatingunits selected from the group consisting of:

[0025] wherein p is 3 to 8 and each R′ may be the same or different andare individually selected from the group consisting of hydrogen andalkyl having from 1 to 5 carbon atoms, such that at least three of saidR₁, R₂ . . . R_(n+1) groups are other than hydrogen;

[0026] m is sufficient such that the star polymer has an inherentviscosity in HFIP at 25° C. between about 0.01 and about 0.5 dl/gm,preferably from about 0.15 to about 0.3 dl/gm; and most preferably fromabout 0.15 to about 0.2 dl/gm, and

[0027] the m's for each Z group may be the same or different.

[0028] The viscosity of the polymer, which is reflective of a number offactors including molecular weight, can be chosen to provide easierprocessing for different applications. Thus, for example, where thepolymers are to be used for coatings or to form a bone wax, viscositiesin the range of 0.15 to 0.2 dl/gm (coinciding to a molecular weight inthe range of about 15,000 to about 25,000 are particularly useful. Whenusing the polymers as a bone substitute, viscosities in the range ofless than about 0.1 dl/gm (corresponding to a molecular weight of 500 to2,000) are particularly useful.

[0029] The purified monomer(s) used to form the Z groups are preferablydried and then polymerized at temperatures ranging from about 20° C. toabout 130° C., preferably above 75° C., in the presence of anorganometallic catalyst such as stannous octoate, stannous chloride,diethyl zinc or zirconium acetylacetonate. The polymerization time mayrange from 1 to 100 hours or longer depending on the otherpolymerization parameters but generally polymerization times of about 12to about 48 hours are employed. In addition, a polyhydric alcoholinitiator is employed to provide a highly branched or star structure.Any polyhydric alcohol may be employed, with mannitol (C₆H₈(OH)₆),pentaerythritol (C(CH₂OH)₄) threitol (C₄H₆(OH)₄) being preferred.Generally, the amount of initiator used will range from about 0.01 toabout 30 percent by weight based on the weight of the monomer. Theamount of initiator employed will depend on the final properties desiredin the polymer and the ultimate end use of the polymer. Thus, whenpreparing polymers for use as a coating, the initiator will be presentin the reaction mixture in an amount from about 0.5 to about 5.0 weightpercent based on the weight of the monomer. When preparing polymers foruse as a bone substitute, the initiator will be present in an amountfrom about 15 to about 25 weight percent based on the weight of themonomer.

[0030] The polymeric chains (Z groups) may be formed using any monomerknown to form a bioabsorbable polymer, however, preferably monomers ofthe type know as soft segments forming polymers constitute thepredominant component (i.e., constitute more than SO mole percent) ofthe polymeric chains. Thus, for example, the polymeric chains may beformed predominantly from E-caprolactone, alkylene carbonates such astrimethylene carbonate; substituted alkylene carbonates such as dimethyltrimethylene carbonate (DMTMC); and/or p-dioxanone. When the polymers ofthis invention are used without isocyanate endcapping (as described morefully hereinafter), homo- or copolymers of DMTMC and homopolymer ofp-dioxanone are preferred.

[0031] Particularly useful polymers are those wherein the Z groupsconsist essentially of repeating units derived from monomer having theformula:

[0032] The monomer can be prepared using known techniques such as, forexample, those processes described in U.S. Pat. Nos. 2,900,345;3,119,840; 4,070,315 and 2,142,033, the disclosures of which areincorporated by reference. A preferred method of preparing the monomeris by dehydrogenating diethylene glycol in the presence of acopper/chromium catalyst.

[0033] The monomer should be purified, preferably to at least about 98percent purity. The monomer may be purified using any known techniquesuch as multiple distillations and/or recrystallizations. A preferredpurification process is recrystallization from ethyl acetate asdescribed in U.S. Pat. No. 5,391,768 the disclosure of which isincorporated herein by reference.

[0034] Polydioxanone star polymers can be made by reacting p-dioxanonemonomer with mannitol initiator in the presence of stannous octoatecatalyst. The reaction is allowed to continue until a polydioxanne chainis bound to three or more hydroxy groups per molecule of mannitol. Theresulting polydioxanone star polymer can be represented by the followingformula:

[0035] where the value of x, y and z for the polydioxanone chains may bethe same or different so long as the product has an inherent viscositybetween about 0.01 deciliters per gram and about 0.5 deciliters per gramin hexafluoroisopropanol (HFIP) at 25° C.

[0036] Polymers of p-dioxanone are not soluble in common organicsolvents. An advantage of the polymer described herein is that it issoluble in methylene chloride. Thus it is easily used as a coating.

[0037] The polymerization parameters are controlled to provide a polymerhaving an inherent viscosity between about 0.01 and 0.5 dl/gram in HFIPat 25° C. It is within the purview of those skilled in the art todetermine the appropriate polymerization parameters to provide polymershaving the desired inherent viscosity in view of the disclosure herein.

[0038] The polymers described herein can be used as an absorbablecoating for surgical devices formed from using any known technique, suchas, for example, extrusion, molding and/or solvent casting. The polymerscan be used alone, blended with other absorbable compositions, or incombination with non-absorbable components. A wide variety of surgicalarticles can be coated with the polymers. These include but are notlimited to clips and other fasteners, staples, sutures, pins, screws,prosthetic device, wound dressings, drug delivery devices, anastomosisrings, and other implantable devices. Fibers coated with the presentpolymers can be knitted or woven with other fibers, either absorbable ornonabsorbable to form meshes or fabrics.

[0039] The star polymers described herein may advantageously beendcapped with isocyanate groups.

[0040] Isocyanate endcapping can be achieved by reacting the polymerwith a diisocyanate. Suitable diisocyanates include hexamethylenediisocyanate, diisocyanatolysine ethyl ester and butane diisocyanatewith diisocyanatolysine ethyl ester being preferred. Diisocyanates whichmay lead to harmful by-products upon hydrolysis of the polymer, such as,for example, certain aromatic diisocyanates, should not be employedwhere the composition is intended for use within a mammalian body. Whileendcapping with diisocyanate is preferred, it is also contemplated thatother agents having at least two reactive sites can be employed forendcapping and for facilitating cross-linking. Suitable other endcappingagents include, for example diketene acetals such asbis-vinyl-2,4,8,10-tetraoxyspiroundecane.

[0041] The conditions under which the polymer is reacted with thediisocyanate may vary widely depending on the specific polymer being endcapped, the specific diisocyanate being employed, and the desired degreeof end capping to be achieved. Normally, the polymer is heated to atemperature sufficient to form viscous liquid (e.g., to temperatures ofabout 75° C. for p-dioxanone homopolymers) and added dropwise to asolution of the diisocyanate at room temperature with stirring. Theamount of diisocyanate employed can range from about 2 to about 8 molesof diisocyanate per mole of polymer. Suitable reaction times andtemperatures range from about 15 minutes to 72 hours or more attemperatures ranging from about 0° C. to 250° C.

[0042] Once endcapped with isocyanate, the polymers may advantageouslybe cross-linked. Cross-linking is normally performed by exposing theendcapped polymer to water in the presence of a catalyst, such as atertiary amine catalyst.

[0043] The exact reaction conditions for achieving cross-linking willvary depending on a number of factors such as the composition of thepolymer, the degree of endcapping, the specific isocyanate used to endcap and the desired degree of cross-linking. Normally, the cross-linkingreaction is conducted at temperatures ranging from 20° C. to about 40°C. for five minutes to about 72 hours or more. The amount of wateremployed will normally range from about 0.05 moles to 1 moles per moleof polymer. While water is a preferred reactant to effect cross-linkingit should be understood that other compounds could also be employedeither together with or instead of water. Such compounds includediethylene glycol, polyethylene glycol and diamines, such as, forexample, diethylamino propanediol. Suitable catalysts for use in thecross-linking reaction include 1,4 diazobicyclo [2.2.2] octane,triethylamine, and diethylaminoethanol.

[0044] The amount of catalyst employed can range from about 0.5 grams toabout 50 grams per kilogram of polymer being cross-linked.

[0045] When the composition is intended for implantation it is possibleto effectuate cross-linking in situ using the water naturally present ina mammalian body or with added water.

[0046] The isocyanate endcapped polymers can also be cross-linked by theapplication of heat alone, or by exposing the polymer to diamine vapor.These cross-linking techniques are particularly useful when the polymersare to be used as a filament coating.

[0047] In an alternative embodiment, the isocyanate endcapped polymersdescribed herein are admixed with a filler prior to cross-linking. Whileany known filler may be used, hydroxyapatite, tricalcium phosphate,bioglass or other bioceramics are the preferred fillers. Normally, fromabout 10 grams to about 400 grams of filler are mixed with 100 grams ofpolymer. Cross-linking of the polymer/filler mixture can be carried outusing any of the above-described methods. The filled, cross-linkedpolymers are useful, for example, as a molding composition. As anotherexample, the filled endcapped polymer (with or without crosslinking) canbe packed into a bone fusion implant (e.g., fusion cage, plug, hip jointprosthesis, etc.) as a bone-growth-inducing substance. The use of suchpacked implants are disclosed, for example, in U.S. Pat. No. 5,026,373the disclosure of which is incorporated herein by this reference. Thefilled polymers are stable for several months when kept dry. These drymixtures will cross-link upon exposure to water without dispersing inwater.

[0048] In another embodiment, an isocyanate endcapped star polymer ischemically altered to provide a desired charge on the polymer. Thepresence of charged groups on the polymer can enhance wound healing ineither hard or soft tissue. To impart a positive charge, the endcappedpolymer may be reacted with a positive charge inducing reactant. Onesuitable positive charge inducing reactant is diethylethanolamine whichresults in the presence of diethylaminoethyl (DEAE) groups on thepolymer. To impart a negative charge, the endcapped polymer may bereacted with a negative charge inducing reactant. One such reactant iscarboxymethanol which results in the presence of carboxymethyl (CM)groups on the polymer.

[0049] The conditions at which the charge inducing reactant is reactedwith the isocyanate endcapped polymer will vary depending on thespecific polymer, the degree of endcapping, the nature of the isocyanateused for endcapping and the number of charges to be provided on thepolymer. Normally, from about 0.1 to about 0.5 moles of charge inducingreactant are employed per mole of isocyanate groups. The polymer isnormally dissolved in a solvent and added dropwise to a solution of thecharge inducing reactant. Stirring and heating to temperatures up toabout 40° C. can facilitate the reaction.

[0050] It is also contemplated that the isocyanate endcapped polymer canbe mixed with a material known to carry a charge to provide a chargedcomposition which enhances wound healing. Such materials includepolysaccharides modified to include charge inducing substituents suchas, for example, carboxymethyl or diethylaminoethyl groups. The weightratio of modified polysaccharide to polymer should be in the range ofabout 1 to about 20%, preferably about 5 to about 10%. DEAE-Sephadex isa particularly useful material to be mixed with the bioabsorbablepolymers described herein.

[0051] In another embodiment, isocyanate endcapped star polymer andfiller are first mixed together as disclosed hereinabove and thereaftercharge inducing reactant is added to the mixture in the same manner asdisclosed hereinabove. It has been found that these mixtures ofisocyanate endcapped star polymer, filler and charge inducing reactantare stable for several months and more when stored under dry conditions.

[0052] It should be understood that for polymers of the embodimentshaving an induced charge and/or endcapped with a lysine isocyanate, anybioabsorbable polymer may be employed. Preferred bioabsorbable polymersaccording to this embodiment are those having the general formula:

CH₂OR₁—(CHOR₂)—(CHOR₃) . . . (CHOR_(n))—CH₂OR_(n+1)

[0053] wherein:

[0054] n equals 1 to 13;

[0055] R₁, R₂ . . . R_(n+1) are the same or different and selected fromthe group of a hydrogen atom or Z wherein Z comprises repeating unitsselected from the group consisting of glycolide, lactide, p-dioxanone,ε-caprolactone and alkylene carbonate units;

[0056] at least three of said R₁, R₂ . . . R_(n+1) groups being otherthan hydrogen;

[0057] at least one of said Z groups being endcapped with an isocyanate;and

[0058] at least a portion of said endcapped Z groups having diethylaminoethyl group thereon.

[0059] Other suitable bioabsorbable polymers which may be endcapped withisocyanate include polyalkylene oxides containing a major amount, i.e.,greater than 50 weight percent, of alkylene oxide units such as ethyleneoxide units, propylene oxide units and combinations thereof and a minoramount, i.e., less than 50 weight percent, preferably less than about 20weight percent, more preferably less than about 5 weight percent, unitsderived from a bioabsorbable monomer such as glycolide, lactide,glycolic acid, lactic acid, p-dioxanone, trimethylene carbonate,trimethylene dimethylene carbonate, dioxepanone, alkylene oxalates,epsilon-caprolactone, combinations of the foregoing, and the like. Thepolyalkylene oxides can be linear or branched random, block or graftcopolymers. The polyalkylene oxides employed herein will generally be oflow molecular weight, e.g., the polymer will possess a molecular weightof less than about 6,000.

[0060] It has also been discovered that novel polymers in accordancewith this disclosure can serve as a substrate for is cell growth.Specifically, star polymers endcapped with lysine diisocyanate andcross-linked, with or without an induced charge, can be used as a cellgrowth substrate.

[0061] When being used for cell growth, the polymers described hereincan also be mixed with collagen, gelatin or other growthproliferating/enhancing materials.

[0062] In yet another embodiment, the isocyanate capped star polymer isreacted with an alkylene oxide polymer. In this manner, hydrophilicpendent chains are formed from at least a portion of the isocyanategroups on the polymer. Preferably, at least a portion of the isocyanategroups remain available for cross-linking. Suitable polyalkylene oxidesinclude polyethylene oxide, polypropylene oxide and block copolymers ofpolyethylene oxide and polypropylene oxide. The alkylene oxide sidechains reduce cell adherence while maintaining the biodegradability ofthe polymer.

[0063] It is further contemplated that one or more medico-surgicallyuseful substances, e.g., those which accelerate or beneficially modifythe healing process when particles are applied to a surgical repairsite, can be incorporated into surgical devices made from the materialsdescribed herein. So, for example, the surgical device can carry atherapeutic agent which will be deposited at the repair site. Thetherapeutic agent can be chosen for its antimicrobial properties,capability for promoting repair or reconstruction and/or new tissuegrowth. Antimicrobial agents such as broad spectrum antibiotic(gentamicin sulfate, erythromycin or VX glycopeptides) which are slowlyreleased into the tissue can be applied in this manner to aid incombating clinical and sub-clinical infections in a tissue repair site.To promote repair and/or tissue growth, one or several growth promotingfactors can be introduced into the sutures, e.g., fibroblast growthfactor bone morphogenetic protein, epidermal growth factor, plateletderived growth factor, macrophage derived growth factor, alveolarderived growth factor, monocyte derived growth factor, magainin, and soforth. Some therapeutic indications are: glycerol and tissue or kidneyplasminogen activator to cause thrombosis, superoxide dimutase toscavenge tissue damaging free radicals, tumor necrosis factor for cancertherapy or colony stimulating factor and interferon, interleukin-2 orother lymphokine to enhance the immune system. It is also contemplatedthat the medico-surgically useful substance may enhance bloodcoagulation. Thrombin is one such substance.

[0064] It is further contemplated that the isocyanate cappedpolyalkylene oxide polymer described above can be combined withtherapeutic agents, preferably charged oxidized beads, e.g.,cross-linked dextran, which are commonly employed to promote woundhealing. The above mixture of hydrophilic isocyanate capped polyalkyleneoxide and therapeutic agent can be reacted with any of theaboveidentified isocyanate capped star polymers prior to introduction tothe wound site to form a polymer network that entraps the therapeuticagent. Upon placement of the polyalkylene oxide/isocyanate capped starpolymer network in the wound, the liquid present at the wound sitecauses the polymer network to swell; thereby allowing delivery of thetherapeutic agent through either diffusion or degradation of the polymernetwork.

[0065] The following non-limiting Examples illustrate the preparation ofpolymers in accordance with the present disclosure.

EXAMPLES 1-3

[0066] 100.0 grams of purified p-dioxanone (99.5% purity) is placed in apolymerization tube. Then 0.02 (w/w) Sn(Oct)₂, i.e., weight of Sn(Oct)₂to weight of polydioxanone, in diethyl ether is added to the tube anddried for two hours under vacuum at 25° C. In addition, the followingamounts of the indicated initiator is added to the vessel: Example No.Initiator Amount 1 Mannitol 1.0 gram 2 Mannitol 2.0 grams 3 Threitol 2.0grams

[0067] Polymerization is conducted at 100° C. for 24 hours. Theresulting polymer is heated to 75° C. at reduced pressure (0.5 mmHg) toremove any residual monomer or other volatile impurities. The polymersproduced have the following inherent viscosities in HFIP at 25° C.:Example No. Inherent Viscosity 1 0.83 2 0.77 3 0.39

EXAMPLES 4-7

[0068] 75 grams of p-dioxanone (99.5%=purity) is placed in apolymerization tube. Then, 0.015% (w/w) Sn(Oct)₂, i.e., weight ofSn(Oct)₂ to weight of polydioxanone, in diethyl ether is added to thetube and dried for two hours under vacuum at 25° C. In addition, thefollowing amounts of the indicated initiator is added to the vessel:Example No. Initiator Amount 4 Mannitol 1.0 gram 5 Mannitol 0.5 grams 6Threitol 1.5 grams 7 Threitol 0.75 grams

[0069] Polymerization is conducted for 24 hours at 100° C. The resultingpolymers are particularly useful for coatings on braided absorbablesutures.

EXAMPLE 8

[0070] A star copolymer of p-dioxanone and glycolide is prepared asfollows: 458.3 grams of previously dried p-dioxanone, 41.7 grams ofpreviously dried glycolide, 147.5 grams of mannitol, and 0.106 grams ofstannous octoate catalyst are reacted in a N₂ atmosphere under anhydrousconditions in a one liter 3 neck flask equipped with a mechanicalstirrer.

[0071] The flask is heated overnight at 98° C. with stirring at 60 rpm.The mixing rate is increased to 100 rpm after about 12 hours ofreaction. After 20 hours, the temperature is reduced to 90° C. Thestirring rate is further increased to 200 rpm after a total of 22 hoursof reaction time. After a total reaction time of about 39 hours, thematerial is extruded at 94°±4° C. The flask is placed under vacuum for 6hours and the polymer is post-treated by heating at 75° C. for about 63hours. A total weight of 599.5 grams of polymer is recovered.

[0072] The product of Example 8 is useful as a bone substitute. The lowviscosity absorbable polymer can be worked by hand and applied directlyto a bone defect to achieve hemostasis.

[0073] The following non-limiting Examples illustrate the endcapping ofpolymers in accordance with this invention:

EXAMPLE 9

[0074] Preparation of Star Copolymer

[0075] A star copolymer of p-dioxanone and glycolide is prepared asfollows: 458.3 grams of previously dried p-dioxanone, 41.7 grams ofpreviously dried glycolide, 83.5 grams of pentaerythritol, and 0.106grams of stannous octoate catalyst are reacted in a N₂ atmosphere underanhydrous conditions in a one liter 3 neck flask equipped with amechanical stirrer. Polymerization is conducted at 90° C. with stirringfor a total reaction time of about 69 hours. The copolymer is thenextruded and heated at 75° C. for 48 hours to remove vaporizableimpurities.

[0076] Preparation of Lysine Diisocyanate Compound

[0077] A five 1 round bottom flask equipped with a mechanical stirrer,condenser and thermometer is dried by heating to >100° C. under nitrogenpurge. After cooling the reactor is charged with 500.0 g lysine ethylester dihydrochloride (I) and 4000 ml 1,1,1,3,3,3-hexamethyl disilazane(II). The slurry is heated to 117° C. for 24 hours, cold and filteredthrough Celite to remove the silazane hydrochloride salt. Afterfiltration excess disilazane (II) is removed under vacuum at roomtemperature leaving a clear light pink liquid (III). This product ispurified by distillation at <50 mT. 325 ml of a light yellow liquid isobtained between 120 and 130° C. (Yield: 295 g, 48%)

[0078] A five-liter round bottom flask equipped with a mechanicalstirrer, 1 liter addition funnel and thermometer is dried by heatingto >100° C. under nitrogen purge. After cooling the reactor is chargedwith 2500 ml anhydrous ether, 245 ml triethyl amine and 317 ml of thepreviously obtained reaction product (III). In a separate dry flask 189g of triphosgene is combined with 1250 ml of ether and stirred undernitrogen until a clear solution is obtained. This solution istransferred to the addition funnel and added dropwise to the solution inthe flask at −20° C. After the addition is complete the reaction isallowed to warm to room temperature and stirred for 40 hrs. At the endof this time the solution is filtered to remove the TEA hydrochloridesalt and placed on the rotovap to reduce the volume. A simpledistillation at <200 mT results in a purified product received between107 and 110° C. The clear, colorless liquid weights 125 g, (60% yield).The total yield is 29%.

[0079] The reaction sequence can be schematically represented asfollows:

[0080] Preparation of Lysine Isocyanate Endcapped Polymer

[0081] A 500 ml round bottom flask is dried by heating under a nitrogenpurge. 57.6 grams of the lysine diisocyanate prepared as described aboveand 28.6 grams of the star dioxanone/glycolide copolymer are added tothe flask. The reactants are heated to and maintained at 60° C. for sixhours. 82 grams of lysine isocyanate endcapped polymer are obtained.

EXAMPLE 10

[0082] A star copolymer of dioxanone and caprolactone is prepared byreacting 250 grams of p-dioxanone with 250 grams c-caprolactone and 36grams of mannitol in the presence of a stannous actuate catalyst at 135°C. for 72 hours. The resulting polymer is then heated at 75° C.overnight. 25 grams of the polymer is dissolved in 125 ml of methylenechloride. Hexamethylene diisocyanate (25 ml) is mixed with 50 ml ofmethylene chloride. The polymer solution is added dropwise to thehexamethylene diisocyanate solution with stirring. The reaction mixtureis maintained at the boil with continuous stirring overnight (about 24hours). The resulting endcapped polymer is the precipitated in hexaneand recovered by decanting the solvent. Excess solvent is removed byevaporation.

EXAMPLE 11

[0083] A homopolymer of DMTMC is prepared by placing 500 grams DMTMC ina reactor with 14 grams of pentaerythritol initiator and 0.01 grams ofstannous octoate catalyst. Polymerization is allowed to occur at 150° C.for 24 hours. The resulting polymer is heated at 90° C. and >0.5 mmHgfor 48 hours to remove residual monomer and other volatile impurities.

[0084] 45 grams of the DMTMC polymer is dissolved in 50 ml methylenechloride and is added dropwise to 100 grams hexamethylene diisocyanate.The mixture is stirred at room temperature for 48 hours. The resultingendcapped DMTMC polymer is washed twice with hexane and dried.

[0085] The following Example illustrates the use of the cross-linkedpolymers as a coating for sutures.

EXAMPLE 12

[0086] Five grams of the endcapped polymer of Example 1 are dissolved in100 ml of methylene chloride. The polymer solution is applied to anabsorbable mdnofilament suture. The coated suture is heated tosimultaneously drive off solvent and effectuate cross-linking of thepolymer coating. The monofilament coated in this manner exhibits greaterin vivo strength retention compared to uncoated monofilaments of thesame size and composition.

[0087] The following Examples show filled cross-linked polymers usefulas a bone-putty.

EXAMPLE 13

[0088] Ten grams of the isocyanate endcapped polymer of Example 9 ismixed with 5 grams of hydroxyapatite. Once a substantially homogenousmixture is attained, the polymer is cross-linked by the addition of 0.5ml of water, 1 ml of DEAE and 0.5 ml stannous octoate. As the reactionproceeds, CO₂ is released, forming a moldable foam which has a puttylikeconsistency and can be molded by hand into a desired shape or easilypacked into a bone defect.

EXAMPLES 14-18

[0089] 10 grams of isocyanate endcapped star copolymer of Example 9 ismixed with 5.0 grams of hydroxyapatite until a substantially homogeneousmixture is obtained in the form of a white paste. Various formulationsof bone putty are produced by adding water, stannous octoate, anddiethylethanolamine to 1.0 gram of the hydroxyapatite/endcapped starcopolymer paste. These formulations are presented in the followingtable: Hydroxyapatite Example Copolymer Increase No. of Ex. 9 H₂OSn(Oct)₂ DEAE in Volume 14 1.0 gram 1 drop 2 drops 2 drops 2X 15 1.0gram 1 drop 2 drops 3 drops 3X 16 1.0 gram 1 drop 3 drops 3 drops 3X 171.0 gram 1 drop 3 drops 2 drops 4X 18 1.0 gram 1 drop 4 drops 7 drops 2X

[0090] Each formulation hardens to provide structural support to aid inhard tissue healing. The bone putty of Examples 16-18 becomes hard tothe touch in 10 minutes or less.

EXAMPLE 19

[0091] A modified bone putty is prepared as follows: 6.1 grams ofcalcium phosphate tribasic are mixed with 3.2 grams of hydroxyapatite.15 grams of endcapped star copolymer of Example 10 are added to thecalcium phosphate tribasic/hydroxyapatite mixture.

[0092] 1.0 gram of the endcapped star copolymer/calcium phosphatetribasic/hydroxyapatite composition is placed into a scintillation vial.Two drops of a 2:1 diethylethanolamine/H₂O mixture and 2 drops ofSn(Oct)₂ catalyst solution are added to the vial. The resultingcomposition is placed into a tibia-bone defect, where it foams with therelease of CO₂, absorbs blood and hardens to provide structural supportto the bone.

[0093] The following Examples show the use of the present polymer as asubstrate for cell growth.

EXAMPLES 19-23

[0094] The endcapped polymer of Example 9 is mixed with various amountsof DEAE solution as set forth in the following Table: Example PolymerDEAE Concentration DEAE No. (gms) (drops) (grams/drop) 19 .35 0 N/A 20.33 5 .07 21 .31 3 .10 22 .42 2 .21 23 .27 1 .027

[0095] The polymers are coated onto one half of a 5 cm tissue cultureplate and allowed to cure for two days. Mouse fibroblasts (L929) aretrypsinized and seeded onto the plates. The cells are grown in minimalessential media with 10% fetal calf serum. The medium was changed after1,4 and 7 days. Cell growth was observed on both the uncoated and coatedhalf of the tissue culture plate, indicating that the present polymersare a suitable substrate for cell growth.

[0096] The following Example shows the preparation of a polymer ofanother embodiment.

EXAMPLE 24

[0097] 10 grams of the lysine isocyanate capped polymer of Example 9 areplaced into a reaction vessel with 9 grams of poly(ethylene oxidemonomethylether) (Mol. Wt. 350) and 0.0038 grams stannous octoate. Thereactants are stirred at ambient temperature for 4 hours. The resultingpolymer is recovered as a viscous liquid which can be applied directlyto a wound site.

EXAMPLE 25

[0098] 20.6 g of diisocyanatolysine ethyl ester was placed in a clean,dry 100 mL round bottomed flask equipped with stirrer and N₂ flow. Thematerial was allowed to dry. A 95:5 weight percentpolyethyleneoxide-glycolide copolymer (1000 molecular weight) was placedunder vacuum for about 1 hour. The polymer was then added dropwise tothe diisocyanatolysine ether ester via syringe to provide anisocyanate-endcapped material.

EXAMPLE 26

[0099] The lysine-diisocyanate endcapped star dioxanone/glycolidecopolymer obtained in EXAMPLE 9 is applied to tissue as an adhesive. Thematerial is placed between tissue to be joined and is of sufficientlylow viscosity to enter small crevices and interstices present in thetissue. Water present in the tissue causes the endcapped polymer tocross-link in situ and cure to a solid. In this matter, the curedencapped polymer provides a mechanical interlocking function whicheffectively maintains the tissue in the desired, joined configuration.

EXAMPLE 27

[0100] A bone substitute material is prepared by mixing 0.55 grams ofthe encapped star copolymer obtained in EXAMPLE 9 with 1.65 grams offine grained b-TCP. Both the copolymer and TCP were previously dried at145° C. for 2 hours under vacuum prior to mixing. Then, 38.5 ml of DEAEis added to the mixture. The resulting material is packaged in asubstantially dry state within a foil or other water-impermeablepackage. In this state, the product is stable for several months. Whenneeded, the package is opened and the product is packed into bone. Uponcontact with water naturally present or added, CO₂ gas is generated sothat when the material hardens a rigid, porous material is thenprovided, giving structural support to aid in hard tissue healing. Overtime, the biodegradable polymer is replaced with new bone tissue growinginto the porous bone substitute.

EXAMPLE 28

[0101] The material of EXAMPLE 27 is further mixed with excesslysine-diisocyanate (110 ml) which increases the amount of CO₂ generatedupon implantation thus increasing the number of pores in the resultingbone substitue. In this manner, the porosity of the bone substitute canbe adjusted as desired.

[0102] It will be understood that various modifications may be made tothe embodiments disclosed herein. For example, the compositions inaccordance with this disclosure can be blended with other biocompatible,bioabsorbable or non-bioabsorbable materials. Therefore, the abovedescription should not be construed as limiting, but merely asexemplifications of preferred embodiments. Those skilled in art willenvision other modifications within the scope and spirit of the claimsappended hereto.

What is claimed is:
 1. A bone fusion device comprising: a) an implant tobe inserted into bone; and b) a bone-growth inducing substance on asurface of the implant, the bone-growth inducing substance comprising acopolymer containing a major amount of alkylene oxide units and a minoramount of units derived from a bioabsorbable monomer selected from thegroup consisting of glycolic acid, glycolide, lactic acid, lactide,p-dioxanone, trimethylene carbonate, trimethylene dimethylene carbonate,dioxepanone, alkylene oxalates, epsilon-caprolactone, and combinationsthereof, said copolymer being endcapped with at least one lysineisocyanate group.
 2. A bone fusion device as in claim 1 wherein theimplant is selected from the group consisting of fusion cages, plugs,and hip joint prostheses.
 3. A bone fusion device as in claim 1 whereinthe isocyanate group is derived from diisocyanatolysine ethyl ester. 4.A bone fusion device comprising: a) an implant to be inserted into bone;and b) a bone-growth inducing substance on a surface of the implant, thebone-growth inducing substance comprising a composition containing aplurality of lysine-based isocyanate endcapped absorbable star polymermolecules, said absorbable star polymer molecules including repeatingunits derived from one or more monomers selected from the groupconsisting of p-dioxanone, alkylene carbonates and mixtures thereof andsaid plurality of star polymer molecules having at least one terminal,reactive isocyanate group and being capable of undergoing cross-linkingwith each other when exposed to water thereby curing to provide a solidmaterial.
 5. A bone fusion device as in claim 4 wherein the implant isselected from the group consisting of fusion cages, plugs, and hip jointprosthesis.
 6. A bone fusion device as in claim 4 wherein the absorbablestar polymer molecules include repeating units derived from dioxanone.7. A bone fusion device as in claim 6 wherein the absorbable starpolymer molecules further include repeating units derived frome-caprolactone.
 8. A bone fusion device as in claim 4 wherein theabsorbable star polymer molecules further include repeating unitsderived from alkylene carbonates.
 9. A bone fusion device as in claim 4wherein the bone-growth inducing substance further comprises a filler.10. A bone fusion device as in claim 9 wherein the filler is abioceramic.
 11. A bone fusion device comprising: a) an implant to beinserted into bone; and b) a bone-growth inducing substance comprising afluid composition containing a plurality of lysine-based isocyanateendcapped absorbable star polymer molecules wherein the plurality oflysine-based isocyanate endcapped absorbable star polymer molecules havethe general formula: CH₂OR₁—(CHOR₂)—(CHOR₃)—(CHOR.₄) . . .(CHOR_(n))—CH₂OR_(n+1) wherein: n equals 3, 4 or 5; R₁, R₂ . . . R_(n+1)are the same or different and selected from the group of a hydrogen atomor (Z)m wherein Z can be different at each occurrence and comprisesrepeating units selected from the group consisting of:

and combinations thereof, wherein p is 3 to 8 and each R′ may be thesame or different and are individually selected from the groupconsisting of hydrogen and alkyl having from 1 to 5 carbon atoms, suchthat at least three of said R₁, R₂ . . . R_(n+1) groups are other thanhydrogen; m is sufficient such that the star polymer has an inherentviscosity in HFPl at 25° C. between 0.05 and about 0.5 dl/gm; the m'sfor each (Z) group may be the same or different; and at least one ofsaid (Z)m groups being endcapped with a lysine based isocyanate andcontaining a terminal, active isocyanate group, and wherein saidplurality of star polymer molecules are capable of undergoingcross-linking with each other when exposed to water thereby curing toprovide a solid material.
 12. A bone fusion device as in claim 11wherein the implant is selected from the group consisting of fusioncages, plugs, and hip joint prosthesis.
 13. A bone fusion device as inclaim 11 wherein the bone-growth inducing substance further comprises afiller.
 14. A bone fusion device as in claim 13 wherein the filler is abioceramic.
 15. A coated surgical device comprising: a) a surgicalarticle possessing a surface to be coated; and b) a coating comprising acopolymer containing a major amount of alkylene oxide units and a minoramount of units derived from a bioabsorbable monomer selected from thegroup consisting of glycolic acid, glycolide, lactic acid, lactide,p-dioxanone, trimethylene carbonate, trimethylene dimethylene carbonate,dioxepanone, alkylene oxalates, epsilon-caprolactone, and combinationsthereof, said copolymer being endcapped with at least one lysineisocyanate group.
 16. A coated surgical device as in claim 15 whereinthe surgical article is selected from the group consisting of clips,fasteners, staples, sutures, fibers, pins, screws, prosthetic devices,wound dressings, drug delivery devices, anastomosis rings and implants.17. A coated surgical device comprising: a) a surgical articlepossessing a surface to be coated; and b) a coating comprising acomposition containing a plurality of lysine-based isocyanate endcappedabsorbable star polymer molecules, said absorbable star polymermolecules including repeating units derived from one or more monomersselected from the group consisting of p-dioxanone, alkylene carbonatesand mixtures thereof and said plurality of star polymer molecules havingat least one terminal, reactive isocyanate group and being capable ofundergoing cross-linking with each other when exposed to water therebycuring to provide a solid material.
 18. A coated surgical device as inclaim 17 wherein the surgical article is selected from the groupconsisting of clips, fasteners, staples, sutures, fibers, pins, screws,prosthetic devices, wound dressings, drug delivery devices, anastomosisrings and implants.
 19. A coated surgical device comprising: a) asurgical article possessing a surface to be coated; and b) a coatingderived from a fluid composition containing a plurality of lysine-basedisocyanate endcapped absorbable star polymer molecules wherein theplurality of lysine-based isocyanate endcapped absorbable star polymermolecules have the general formula: CH₂OR₁—(CHOR₂)—(CHOR₃)—(CHOR₄) . . .(CHOR_(N))—CH₂OR_(N+1), wherein: n equals 3, 4 or 5; R₁, R₂ . . .R_(N+1) are the same or different and selected from the group of ahydrogen atom or (Z)_(m) wherein Z can be different at each occurrenceand comprises repeating units selected from the group consisting of:

and combinations thereof, wherein p is 3 to 8 and each R′ may be thesame or different and are individually selected from the groupconsisting of hydrogen and alkyl having from 1 to 5 carbon atoms, suchthat at least three of said R₁, R₂ . . . R_(n+1) groups are other thanhydrogen; m is sufficient such that the star polymer has an inherentviscosity in HFPI at 25° C. between 0.05 and about 0.5 dl/gm; the m'sfor each (Z) group may be the same or different; and at least one ofsaid (Z)_(m) groups being endcapped with a lysine based isocyanate andcontaining a terminal, active isocyanate group, and wherein saidplurality of star polymer molecules are capable of undergoingcross-linking with each other when exposed to water thereby curing toprovide a solid material.
 20. A coated surgical device as in claim 19wherein the surgical article is selected from the group consisting ofclips, fasteners, staples, sutures, fibers, pins, screws, prostheticdevices, wound dressings, drug delivery devices, anastomosis rings andimplants.
 21. A biocompatible composition comprising a branchedcopolymer containing a major amount of alkylene oxide units and a minoramount of units derived from a bioabsorbable monomer selected from thegroup consisting of glycolic acid, glycolide, lactic acid, lactide,p-dioxanone, trimethylene carbonate, trimethylene dimethylene carbonate,dioxepanone, alkylene oxalates, epsilon-caprolactone, and combinationsthereof, said copolymer being endcapped with at least one group derivedfrom a diketene acetal.